The present invention relates to new guanyl hydrazones and to processes permitting their preparation, also medicaments containing them.
Numerous guanyl hydrazones have been synthesised since the preparation by Thiele of the first guanyl hydrazone, namely benzaldehyde guanyl hydrazone, at the end of the 19th century. Certain of the guanyl hydrazones described in the prior art possess a therapeutic activity, in particular the guanyl hydrazones formed from quinones and heterocyclic aldehydes. The literature describes especially the bacteriostatic and tuberculostatic activity in vitro of substituted guanyl hydrazones, such for example as the mono- and di-guanyl hydrazones of p-quinones. Bisguanyl hydrazones with a high degree of substitution have been described for their properties of combatting malaria. The bactericidal activity of 5-nitrofurfuraldehyde guanyl hydrazone has been described, and certain authors have also shown that this compound possesses a certain anti-tumoral activity in the mouse. The sympatho-mimetic action of certain bisguanyl hydrazones and of the guanyl hydrazone of p-hydroxybenzaldehyde and p-methoxy benzaldehyde has also been described. Substituted benzophenone guanyl hydrazones have been described for their analgesic, spasmolytic and anti-inflammatory activity (when one of the nuclei is substituted by a hydroxy-group) and for their anti-malarial activity (when the nuclei are substituted by one or more atoms of halogen or by groups containing halogen atoms).
The works of E. MUTSCHLER, J. SPRINGER and O. WASSERMANN (Biochemical Pharmacology, vol. 19, pp. 9-15, Pergamon Press 1970) have shown that guanyl hydrazones of various aromatic carbonyl compounds are inhibitors of the MAO (monoamine oxydase) of guinea pig liver mitochondriae, in vitro. Finally works by SARTORELLI et coll. 1965 (reported in G. MATHE, chemotherapy of cancer (leukaemias, haematosarcomas, solid tumours), 2nd edition, Expansion Scientifique Francaise Ed.) have shown that methyl-glyoxal-bis (guanyl hydrazone) forms complexes with ADN and inhibits the synthesis of nucleic acids, and BURCK et coll. 1962 (G. MATHE, ibid. have formulated the hypothesis that it would affect cellular respiration, inhibiting lactic and malic dehydrogenases. Its action has been verified in acute myeloblastic and promyelocytary leukaemias, but it has proved less efficacious in the acute transformations of chronic myeloid leukaemia and in other leukaemias, and sometimes but rarely efficacious in Hodgkin's disease. Its administration is however accompanied by various cutaneous, digestive and metabolic troubles, in particular hypoglycaemia).
The present invention aims at providing for new guanyl hydrazones which are distinguished in particular by their therapeutic properties and especially by their antimitotic, IMAO and platelet anti-aggregant activity.
The present invention has for an object new guanyl hydrazones, characterised in that they respond to the following general formula I: ##STR2## wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5, which may be identical or different, represent atoms of hydrogen, halogen (such as fluorine, chlorine bromine), lower alkyl groups (such as methyl, isopropyl, tert-butyl), alkoxy groups (such as methoxy), the aromatic group which can be mono- or polysubstituted by at least one atom of hydrogen, halogen, a lower alkyl or alkoxy group, and
R and R', which may be identical or different, each represent an atom of hydrogen or a methyl group.
The present invention also relates to the physiologically acceptable salts of these compounds.
The present invention further has for object new medicaments, characterised in that they contain as an active constituent at least one of the guanyl hydrazones according to the present invention.
The present invention likewise has for an object a process for the preparation of these guanyl hydrazones, characterised in that they are prepared by condensation of the corresponding aldehydes or of their diethylacetal with aminoguanidine or with one of the salts of the latter.